The invention relates to compositions of selenium monobromide-oil reaction product and further relates to pharmaceutical compositions containing these reaction products. Methods of making and using such compositions for treating the symptoms of neoplastic conditions are also encompassed.
The antitumoral and antineoplastic activity of selenium derivatives has already been described in earlier patents. For example, U.S. Pat. No. 4,564,634 discloses compositions of selenium incorporated in tung oil, while U.S. Pat. No. 4,681,753 discloses compositions of certain dialkyl diselenides and ketones.
These compositions are effective for the treatment of certain neoplastic conditions, but I have found that pharmaceutical compositions containing a selenium monobromide-oil reaction product in combination and preferably with epichlorohydrin provide improved performance and are effective in treating a wide range of neoplastic conditions.
The invention relates to a composition of selenium monobromide-oil reaction product useful in treating a subject suffering from neoplastic conditions. The selenium monobromide-oil reaction product typically exhibits ultraviolet absorption maxima typical of conjugated trienes and conjugated dienes. The reaction product comprises of selenium monobromide-in-oil which contains at least about 0.1 weight percent of selenium monobromide, prepared from an oil containing eleostearic acid and selenium monobromide.
Pharmaceutical compositions containing these reaction products and a pharmaceutically acceptable carrier are also encompassed by the invention
A process of preparing a selenium monobromide-oil reaction product is another embodiment of the invention. The process comprises reacting sufficient amounts of an eleostearic acid containing oil and selenium monobromide at a sufficient temperature and for a sufficient time to incorporate at least about 0.1 weight percent of selenium monobromide in the oil. The process generally involves reacting about 50 to 150 parts of oil with about 1 to 10 parts of powdered selenium monobromide at a temperature of 200 to 250xc2x0 C. for a period of about 1 to 4 hours, until the reaction product becomes substantially clear, continuing heating the reaction product for about an additional 15 minutes to an hour, and decanting off the selenium monobromide which has not reacted.
A further embodiment is a method of treating a subject affected with a neoplastic condition, such as cancer. The method usually involves administering a therapeutically effective amount of a pharmaceutical composition containing a selenium monobromide-oil reaction product. The pharmaceutical composition is typically administered to the subject 2 to 4 times daily in capsule form, although a combination between oral and intradermal administration is also often used.
The present invention relates to compositions of selenium monobromide-oil reaction product that exhibits a substantial antineoplastic activity. More specifically the invention encompasses compositions comprising a reaction product of selenium momobromide-in-oil prepared from oil containing eleostearic acid and selenium monobromide. The reaction product generally contains at least about 0.1 weight percent selenium monobromide and preferably between about 0.1 to 5 weight percent. Typically the reaction product exhibits ultraviolet absorption maxima associated with conjugated trienes and conjugated dienes.
Generally, any oil containing eleostearic acid can be used. Most preferably, however, the oils containing eleostearic acid in the form of 9, 11, 13-octadecatrienoic acid of formula CH3xe2x80x94(CH2)3xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)7xe2x80x94COOH are preferred.
This acid is a fatty acid and is the chief component in xe2x80x9ctung oil.xe2x80x9d By warming selenium monobromide with oil containing eleostearic acid at a temperature of about 200 to 250xc2x0 C., a selenium monobromide reaction product is formed.
Typically, the percentage of selenium monobromide in compositions prepared in this manner may vary within a broad range, but is preferably between about 0.1 to 5 weight percent for therapeutical use, compounds containing between about 2 to 4 weight percent by weight of selenium monobromide-oil reaction product are particularly useful.
The invention further relates to pharmaceutical compositions for administration to a human subject suffering from a neoplastic condition such as cancer. The pharmaceutical compositions typically include a reaction product of selenium momobromide-in-oil prepared from eleostearic acid and selenium monobromide, and a pharmaceutically acceptable carrier. Advantageously the pharmaceutical composition generally contains at least 0.1 weight percent. Preferably, however, the composition comprises about 0.1 to 5 weight percent of selenium monobromide-oil reaction product, more preferably about 2 to 4 weight percent and most preferably about 3 weight percent. The balance of the composition is usually composed of a pharmaceutically acceptable carrier. A liquid such as an oil, water or saline solution is typically used. If an oil is used as a carrier, vegetable, animal, fish oil, tung oil, sesame oil or combinations thereof can be used. Preferred oils are tung and sesame oils and combinations thereof.
The pharmaceutical composition usually further includes epichlorohydrin to enhance the antineoplastic properties of the reaction product. Epichlorohydrin is often included in an amount of between about 0.1 and 5 weight percent of the composition and more preferably between 0.5 and 1 weight percent. The epichlorohydrin used is preferably hydrolyzed.
Besides epichlorohydrin other epoxy agents can be used together or as an alternative to enhance the antineoplastic properties of the reaction product. Examples include epibromohydrine, 1,2-epoxy butane, 1,2-epoxy, 3 allyloxypropane, epoxyoctoxypropane, and 2,3-epoxypropylacrylate.
The pharmaceutical composition is usually sterilized by heating.
Generally the pharmaceutical composition is prepared as a single dosage form wherein the selenium monobromide-oil reaction product is present in an amount of from about 0.1 ml to 200 ml and more preferably about 05. to 5 ml per unit. Advantageously, a epichlorohydrin solution is present in an amount of from about 0.1 ml to 50 ml and more preferably about 1 to 5 ml per unit.
A further embodiment of the invention relates to a process of preparing a selenium monobromide-oil reaction product from eleostearic acid containing oil and selenium monobromide. The process typically comprises reacting sufficient amounts of an eleostearic acid containing oil and selenium monobromide at a sufficient temperature and for a sufficient time to incorporate at least about 0.1% of selenium monobromide in the oil.
A preferred embodiment of the inventive process consists of warming selenium monobromide with an oil, preferably a combination of sesame and xe2x80x9ctung oilxe2x80x9d up to a point when the mixture becomes clear, so that the elementary selenium monobromide substantially disappears. This process typically consists of reacting 50 to 150 parts, more preferably 75 to 125 parts and most preferably 97 parts oil containing eleostearic acid with 1 to 10 parts, more preferably 2 to 5 parts and most preferably 3 parts of powdered selenium monobromide at a temperature of about 200 to 250xc2x0 C. for a period of about 1 to 4 hours and most preferably about 2 to 3 hours, until the reaction product becomes substantially clear. This is followed by continuing to heat the reaction product for about an additional 15 minutes to hour and most preferably for about a half hour, followed by decanting off the selenium monobromide that has not reacted.
During heating, the mixture is typically oxidized or heated in the presence of oxygen. The oxygen can be obtained by merely heating the formulation open to the atmosphere but preferably and advantageously, the source of oxygen is an oxygen-containing gas, such as air, injected into or bubbled through a heated oil, such as sesame oil/tung oil, according to the invention. The injected gas also serves as a source of agitation to facilitate the oxidation of the oil.
Typically the oil used in this process is a reaction product of an animal, vegetable, or fish oil, or tung oil or sesame oil, or a combination thereof. More preferably tung oil or sesame oil and most preferably a combination of sesame and tung oil are used.
Advantageously, about 0.1 to 5 parts, more preferably 0.5 to 1 part epichlorohydrin can be added to the selenium monobromide-oil reaction product to further enhance its antineoplastic properties.
The epichlorohydrin used is preferably hydrolyzed. The hydrolyzed epichlorohydrin is prepared by heating the epichlorohydrin in water to provide the aqueous solution of epichlorohydrin; and the method further comprises combining a therapeutically effective amount of selenium monobromide-oil reaction product with the epichlorohydrin solution.
A further embodiment of the invention relates to a method of treating a subject affected with a neoplastic condition, such as cancers, sarcomas, lymphomas and leukemias. The method generally comprises the step of administering a therapeutically effective amount of a pharmaceutical composition containing a selenium monobromide-oil reaction product at least once daily or more preferably 2 to 4 times daily, depending on the dosage amount and form of administration, until disappearance of the neoplastic condition.
The magnitude of a prophylactic or therapeutic dose of the selenium monobromide-oil reaction product use in the treatment of a subject affected by neoplastic conditions, will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
In general, the total daily dose range, for the conditions described herein, is typically from about 0.1 ml to about 500 ml administered in single or divided doses orally, by injection, topically, transdermally, or locally by inhalation. Preferred administration routes include the oral and injection routes or a combination of the two. For example, a typical oral daily dose range should be from about 0.1 ml to 200 ml, preferably about 1 ml to 100 ml, and more preferably about 2 ml to 50 ml of the active components (i.e., excluding excipients and carriers).
It is further recommended that children, patients aged over 65 years, and those with impaired renal or hepatic function initially receive low doses, and that they then be titrated based on individual response(s) or blood level(s). It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those of ordinary skill in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
The product of the invention have in general a low toxicity, which permits their use in adequately high amounts to treat neoplastic conditions. Good clinical results have been obtained as indicated in the examples below.
Although any suitable route of administration may be employed for providing the patient with an effective dosage of the composition according to the methods of the present invention, preferred routes include, for example, oral and injection, and like forms of administration may be employed. xe2x80x9cInjectionxe2x80x9d typically includes parenteral, intravenous, subcutaneous, and intramuscular routes. Suitable dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, gel-caps, patches, one-shot injections, needleless injectors, and the like, although oral and injectable dosage forms are preferred. A preferred injection route is intramuscularly.
The pharmaceutical compositions used in the methods of the present invention include the active ingredients described above, and may also contain pharmaceutically acceptable carriers, excipients and the like, and optionally, other therapeutic ingredients. The active ingredients used in the methods and compositions can be administered individually, as a single composition that contains all the ingredients, or in any combination thereof.
The compositions for use in the methods of the present invention may be prepared in various formulations, such as suspensions, solutions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets), with the oral capsules and oral liquid preparations being preferred. The most preferred oral solid preparations are capsules.
Because of their ease of administration, capsules represent the most advantageous oral dosage unit form. A capsule may be prepared with one or more accessory ingredients for example epichlorohydrin. Capsules my be prepared by manual or mechanical means with a suitable machine. Desirably, in one embodiment each unit dose, e.g., capsule, contains from about 0.1 mg to 1,000 mg of the active ingredient, preferably about 0.5 mg to 100 mg, and more preferably about 1 mg to 50 mg of the selenium monobromide-oil reaction mixture.
In addition to the common dosage forms set out above, the compounds of the invention can also be administered by controlled-release means or delivery devices that are well known to those of ordinary skill in the art, such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, the disclosures of which are incorporated herein by reference. Preferred controlled-release means are disclosed by: U.S. Pat. Nos. 5,427,798 and 5,486,362; WO 9404138; CA 1239034; and European Patent Application Nos. 467488 and 171457, all of which are incorporated herein by reference. These dosage forms can be used to provide slow or controlled-release of one or more of the active ingredients therein using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the present invention.
The compositions of the invention is used to treat patients with different neoplastic conditions, and might sometimes alleviate some of the symptoms of the condition without necessarily eliminating the disease itself. In application, however, both subjective and objective improvements have been found to be beneficial to the subjects treated with these compositions and are encompassed by the invention.